Angiotensin converting enzyme (peptidyl-dipeptide hydrolase, a dipeptide-liberating exopeptidase hereinafter referred to as ACE) converts the physiologically inactive decapeptide angiotensin I, which has the sequence: EQU AspArgValTyrIleHisProPheHisLeu
(wherein Asp=L-aspartic acid, Arg=L-arginine, Val=L-valine, Tyr=L-tyrosine, Ile=L-isoleucine, His=L-histidine, Pro=L-proline, Phe=L-phenylalanine and Leu=L-leucine) to the most potent naturally occurring pressor substance known--the octapeptide angiotensin II--by catalyzing the hydrolysis of the penultimate peptide bond to effect removal of the carboxyl-terminal HisLeu. ACE also acts as a catalyst for the hydrolysis of the penultimate peptide bond in a variety of acylated tripeptides and larger polypeptides which have an unblocked .alpha.-carboxyl group.
In a second series of reactions, ACE inactivates the powerful vasodepressor bradykinin by catalyzing the hydrolytic release of one or more carboxyl-terminal dipeptides from this nonapeptide.
ACE is not distributed uniformly throughout mammals, whether humans or animals, but instead is concentrated at sites of a few cell types within a relatively small number of tissues. Specifically, the presence of ACE in mammals appears to be largely restricted to endothelial cells of the vascular tree (including the lymphatic system), the brush border epithelium of the kidneys and gut, the testicles, seminal plasma and blood plasma. ACE activity has also been found in the brain, particularly in the brain stem. In some disease states, ACE may also be concentrated in granulomas characteristic of Boeck's sarcoid and in the spleen tissue of patients affected by Gaucher's disease.
In recent years, a number of chemical compounds which act in vivo as enzyme inhibitors, including ones which act as ACE inhibitors, have been synthesized. Certain of these enzyme inhibitors, again including one ACE inhibitor known to the present inventors, have been labeled with radioisotopes [articles by Kripalani et al, Clin. Pharmacol. Ther., 27, 636 (1980) and Wong et al, Pharmacologist, 21, 155 (1979) describe the synthesis of .sup.35 S-3-mercapto-2-D-methylpropanoyl-L-proline (.sup.35 S-captopril) and .sup.14 C-labeled captopril, respectively, for the purpose of studying the disposition of captopril in humans and animals]. And certain of the thus-labeled enzyme inhibitors (although, to the present inventors' knowledge, no ACE inhibitors) have been used to radioimage mammalian sites.
A series of papers by Beierwaltes et al, J. Nucl. Med., 17, 998-1002 (1976); J. Nucl. Med., 19, 200-203 (1978); Seminars in Nuclear Medicine, 8, 5-21 (1978), report on experiments using radiolabeled enzyme inhibitors in attempts to image the adrenal glands in rats, dogs and humans. These studies showed that in some cases, radiolabeling one inhibitor for an adrenocortical enzyme enhanced its uptake by the adrenal cortex, while radiolabeling another adrenocortical enzyme inhibitor markedly decreased its uptake by the target organ. It thus appears from these studies that one cannot know in advance how labeling with a radioisotope will affect tissue uptake and, consequently, the usefulness of an enzyme inhibitor as a radiopharmaceutical for imaging mammalian sites.
Johns et al, J. Nucl. Med., 9, 530-535 (1968) reported on the use of 3'-.sup.135 iodoaminopterin, an inhibitor of dihydrofolate reductase, to radioimage organs where this enzyme is found.
Various radiopharmaceuticals said to be useful for radioimaging mammalian sites are disclosed in U.S. Pat. Nos. 4,243,562; 4,243,652; 4,279,887; 4,316,883; 4,318,898; 4,323,546; 4,350,674 and 4,360,509.